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Principal Investigator: Manoj T Duraisingh
Organization: HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
Fiscal Year: 2024
Award: $60,361
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
We confirm that the scope of the parent grant (R01AI168163) will remain unchanged.
Malaria parasites infect red blood cells (RBCs), within which they proliferate to cause disease in a continuous
cycle of invasion, growth, and egress from one host RBC to another. Free merozoite parasites use ligand-
receptor interactions to invade RBCs and escape the humoral immune system after egress from an infected
RBC. Plasmodium vivax, a parasite that causes malaria, exclusively invades reticulocytes, the youngest RBCs,
through these ligand-receptor interactions. The Duffy antigen receptor for chemokines (DARC) is a blood group
antigen on the RBC surface. DARC was the first identified receptor for P. vivax, binding the parasite protein P.
vivax Duffy Binding Protein (PvDBP). Genetic variations in the DARC gene, which determines the presence or
absence of Duffy antigens, affect malaria control efforts. Duffy-negative populations of African ancestry were
initially thought to resist P. vivax invasion. However, recent studies showed that Duffy-negative cells allow a
low level of DARC expression, primarily on immature reticulocytes, the presumed target of invasion by P. vivax
parasites.
There have been increasing reports of antimalarial drug resistance with P. vivax, which poses a significant
public health concern and impedes malaria control efforts and elimination programs. The mechanisms of drug
resistance in P. vivax are poorly understood, and we hypothesize that drug resistance will be influenced by
invasion into reticulocytes of different ages, cells undergoing dynamic changes to surface receptor
presentation, sub-cellular organelle composition, and metabolic capacity. Given the observation regarding
Duffy-negative invasion into immature reticulocytes, I hypothesize that the invasion of parasites into younger
reticulocytes alters sensitivity to standard antimalarial drugs. Here, I propose to (Aim 1) explore whether P.
vivax invasion into reticulocytes of different ages promotes drug resistance (in reticulocytes with and without
DARC); (Aim 2) identify reticulocyte host receptors for P. vivax using a CRISPR/Cas9-based RBC knockout
screen of candidate membrane receptors. This work is crucial for advancing 1) our knowledge of P. vivax
invasion in Duffy-negative reticulocyte populations and drug resistance mechanisms and 2) identifying novel
reticulocyte-tropic invasion pathways.
Terms: <Affect><African ancestry><African descent><Age><Anti-malarial drug resistance><Anti-malarial drug resistant><Anti-malarials><Antigen Receptors><Antigens><Binding><Binding Proteins><Blood Group Antigens><Blood erythrocyte><Blood reticulocyte><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cas nuclease technology><Cell Body><Cell surface><Cells><Chemokine Receptor Gene><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Development><Diffusely basophilic erythrocyte><Disease><Disorder><Drug Therapy><Drug resistance><Drugs><Erythrocytes><Erythrocytic><Generalized Growth><Genetic Diversity><Genetic Variation><Growth><Immune system><Invaded><Knock-out><Knockout><Knowledge><Ligand Binding Protein><Ligand Binding Protein Gene><Ligands><Malaria><Marrow erythrocyte><Marrow reticulocyte><Medication><Membrane><Metabolic><Molecular><Molecular Interaction><Organelles><P vivax><P. vivax><Paludism><Parasites><Pathway interactions><Pharmaceutical Preparations><Pharmacotherapy><Plasmodium Infections><Plasmodium vivax><Policies><Polychromatophilic Erythrocyte><Population><Predisposition><Proliferating><Protein Binding><Proteins><Public Health><Receptor Protein><Red Blood Cells><Red Cell><Reporting><Research><Resistance><Reticulocytes><Surface><Susceptibility><Tissue Growth><Work><ages><anti-malarial agents><anti-malarial drugs><anti-malarial resistance><blood corpuscles><bound protein><chemokine receptor><developmental><drug resistant><drug treatment><drug/agent><immunogen><insight><membrane structure><novel><ontogeny><parasite invasion><parent grant><pathway><programs><receptor><resistance mechanism><resistance to Drug><resistance to anti-malarial drug><resistant><resistant mechanism><resistant to Drug><resistant to anti-malarial drug>